ABSTRACT Steroid Receptor Coactivator 3 (SRC-3) is a key breast cancer oncogene that is frequently overexpressed or amplified in estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) positive breast cancers. Elevated expression of SRC-3 also has been associated with resistance to tamoxifen therapy and with poor disease outcome in HER2 positive breast cancers. Numerous studies have shown that experimental targeting of SRC-3 can limit breast cancer cell growth and restore the anti-estrogenic actions of tamoxifen. SRC-3 has been well characterized and murine proof of concept studies suggest inhibition of this target will lead to an entirely new class of drugs for a wide range of SRC overexpressing tumors. SRCs are a promising target since they function as coactivators not only for nuclear receptors like ER?, but also as key coactivators for `growth promoting' transcription factors such as such as E2F1, Twist, NfkappaB and others. These transcription factors are lucrative targets for difficult-to-treat tumors such as triple negative breast cancer (TNBC) and hormone refractory breast cancer. Most targeted therapeutic drugs available are designed to inhibit only one pathway. However, drug resistance often occurs when tumors shift to alternative growth pathways, rendering the original targeted pathway non-essential for tumor growth. Inhibiting SRC-3 has implications on multiple relevant cancer signaling pathways simultaneously, and accordingly it is an ideal target for difficult-to-treat cancers. We have identified proprietary small molecules that selectively and potently inhibit SRC-3 protein levels. We have demonstrated that these inhibitors prevent TNBC tumor growth in vivo and effectively kill cancer stem cells. In our preliminary studies, we elucidated the metabolic mechanisms of these inhibitors and developed proprietary derivatives with improved drug-like properties resulting in our current lead molecule SI-12. During this Phase 1 STTR, inspired by our encouraging preliminary study showing that TNBC cell lines with subtypes involving growth factor signaling pathways are more sensitive to SRC-3 inhibition induced toxicity, we will determine the IC50 values of SI-12 in all the TNBC cell lines in the ATCC Breast Cancer Cell Panel (ATCC 30-4500K?) and correlate the IC50 values with the TNBC subtypes. We will also measure the SRC-3 levels in these TNBC cell lines using Western blot with and without SI-12 treatment. We will compare whether a high protein level of SRC-3 in TNBC cell lines is correlated with SI-12 sensitivity and evaluate the ability of SI-12 to block TNBC tumor growth in vivo. In a subset of SI-12 sensitive TNBC cells, we will also determine the changes of cell migration and invasion abilities upon SI-12 treatment. We will then extensively characterize SI- 12 for the shelf stability, in vitro and in vivo ADMET profiles, proteomics based target identification, transcriptome-wide RNA sequencing and PKPD relationship. During Phase II SI-12 will be evaluated in patient derived xenograft breast cancer models representing TNBC tumors and conduct extensive IND-enabling evaluations of SI-12's biodistribution, pharmacokinetics and toxicity.